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Protein kinase inhibitors for targeting tumor‐initiating cells in uveal melanoma
Author(s) -
Cabre Estivill E.,
Pereira E.,
Vinyals A.,
Lorenzo D.,
Varela M.,
Piulats J.M.,
Caminal J.M.,
Fabra À.
Publication year - 2017
Publication title -
acta ophthalmologica
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.534
H-Index - 87
eISSN - 1755-3768
pISSN - 1755-375X
DOI - 10.1111/j.1755-3768.2017.03645
Subject(s) - gnaq , cancer research , melanoma , cd44 , kinase , population , biology , medicine , cell , mutation , microbiology and biotechnology , genetics , environmental health , gene
Purpose Uveal Melanoma ( UM ) is the most common intraocular tumor in adults. Surgery and brachytherapies have improved survival rates, but up to 40% of patients develop liver metastases. Mutations in the Gαq family members GNAQ and GNA 11 are present in 80% of UM tumors whereas BRAF mutations are much less common. Consequently, Protein Kinase signaling pathways are dysregulated and specific targets can be identified for precise therapeutic approach. On the other hand, it has been proposed that tumors contain a specialized subset of cells defined as tumor‐initiating cells ( TIC s) that may be responsible for de novo resistance to drugs and metastatic disease. Thus, targeting TIC s may be imperative for achieving a cure. Methods To this end, we performed an in vitro screening using the Screen‐Well® Kinase Inhibitor Library ( BML ‐2832‐0100) on TIC ‐enriched populations of UM cells harboring either GNAQ / GNA 11 or BRAF mutations. Results These UM ‐ TIC s have the capacity to self‐renew and generate tumor spheres (melanospheres) in low‐adherent culture conditions. Furthermore, they display stem cell‐like features such as high expression of CD 133, CD 44, Nestin or ABCB 5 specific markers. The metastatic ability of OMM ‐2.5‐enriched TIC cells is currently explored in vivo after their orthotopic injection into the uvea of HL ‐ SCID mice.
Our results revealed that metastatic and TIC ‐enriched populations were more resistant to antiproliferative effects of kinase inhibitors. Several kinase inhibitors such as Tyrphostin 51 ( EGFR i), DES ( PKC i), DRB ( CK 2i) and ML ‐9 ( MLCK i) differentially affected growth and survival of TIC ‐enriched population from parental cell line Mel270. Conclusions Taken together, we showed that EGFR , MAPK , PKC and PI 3K signaling pathways are activated in TIC s and their respective inhibitors may represent attractive therapeutic candidates for metastatic UM .